X-linked agammaglobulinemia (XLA) is a congenita antibody deficiency disease with a sex-linked mode of inheritance. The cellular defect which results in this disease has not been identified. While most patients lack B lymphocytes, some XLA patients have B lymphocytes which are not responsive to mitogenic stimulation in short term culture. An EBV transformed B cell line derived from a patient with XLA was found to have a unique phenotype, consisting of predominantly surface IgD bearing cells, a small population of surface IgD and IgM bearing cells, no expression of IgG or IgA, and no detectable production of immunoglobulin for export. The phenotype of this cell line is analogous to the phenotype of early, surface IgD bearing lymphocytes which differentiate into cells secreting all classes of immunoglobulin. Fusion of B lymphocytes from this patient with mouse myeloma cells resulted in hybrid cells producing human IgM, IgG, and IgA. These results demonstrate the presence of functional structural genes for immunoglobulin in this form of XLA, and suggest that these B lymphocytes have a block in differentiation which prevents their progression beyond surface IgD bearing cells. The cellular basis of XLA will be examined. B cell lines derived from other patients will be examined to determine whether the IgD predominant phenotype is characteristic of B lymphocytes from these XLA patients. Clone B cell lines expressing only IgD will be fused to mouse myeloma cells or to mouse B lymphocytes to determine whether hybrid descendants produce human IgM, IgG, and IgA. X-linked regulation of immunodeficiency will be tested by determining whether human, or mouse, immunoglobulin is produced by clones of hybrid cells which retain an active human X-chromosome. Finally, X-linked regulation of immunodeficiency will be tested by determining whether B cell lines derived from the mothers of these patients include surface IgD restricted sublines, and clones, as would be predicted by random X chromosome inactivation (Lyon's hypothesis).